There are many disorders known wherein the proliferation of fibrotic tissue is a characteristic feature. Examples of such disorders include, for example, rheumatoid arthritis, chronic arthritis, osteoarthritis, hepatic fibrosis, hepatic cirrhosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, arteriosclerosis tumour-associated fibrosis and the formation of scar tissue following injury or surgery. Additional examples include disorders related to the over proliferation of connective tissue in such areas systems as the central nervous system. Thus, a therapeutic agent which possesses anti-fibrotic properties may be of value in the treatment of one or more of these disorders.
It is known that the enzyme prolyl 4-hydroxylase is involved in the hydroxylation of proline residues in collagenous protein, and that 4-hydroxyproline residues are essential for the formation of the characteristic triple helical form of collagen which is secreted into fibrotic tissue. Consequently, a compound which inhibits the activity of prolyl 4-hydroxylase may be of potential value in the treatment of fibroproliferative disease, which is characterized by excessive collagen production.
Various chemical compounds have been reported to inhibit prolyl 4-hydroxylase; for example, 2,2'-dipyridyl (W. Muller et al., FEBS Letters, 90:218 (1978)), pyridine-2,4-dicarboxylic acid (K. Majamaa et al., Eur. J. Biochem., 138:239 (1984)), pyridine-2,4-dicarboxlic acid derivatives and pyridine-2,5-dicarboxylic acid deivatives (European Patent Application Nos. 278452, 278453, 278454 and 281943) and heterocyclic carbonylglycines (T. J. Franklin et al., Biochem. Soc. Trans., 19:812-815 (1991)). However, to the extent that these compounds have not been tested in in vivo systems, whether these compounds may be useful in modulating collagen production or permitting the regeneration of cells whose growth or propagation are otherwise inhibited by the presence of collagen overproduction has not been previously determined.
Despite previous efforts, a need exists for safe and effective means for the treatment of fibroproliferative diseases and disorders.